Fast-rotation, multi-detector computed tomography (MDCT) has revolutionized noninvasive coronary angiography. Contrast-enhanced CT of the coronary arteries (CTA) has a high negative predictive value for coronary artery disease (CAD), obviating the need for invasive coronary angiography in symptomatic patients in whom coronary stenoses are not detected during CTA. However, when CTA demonstrates a stenosis there can be significant uncertainty regarding the physiological significance of the lesion. The goal of this proposal is the development of a combined angiographic/myocardial-perfusion MDCT-based diagnostic procedure to both detect coronary lesions and also assess their physiological significance. This will be accomplished with two CT scans, one acquired at rest and a second during pharmacological stress. A major obstacle to the widespread adoption of a combined angiographic/perfusion imaging procedure using conventional techniques is the need to deliver a radiation dose on the order of 10 times that of conventional CTA. This is due to the two extended scans necessary to record the myocardial time-density curve at both rest and during stress. This proposal seeks to develop a combined angiographic/perfusion examination without increasing the dose currently delivered during conventional CTA by using a novel reconstruction algorithm. HighlY constrained backPRojection (HYPR) is an approach to time-resolved tomographic imaging that exploits spatio-temporal correlations to greatly reduce the required number of projections per image. Preliminary studies indicate the potential for HYPR-CT reconstruction to provide dose reduction of at least a factor of 10 compared to conventional cardiac CT imaging. We propose to develop a HYPR-CT algorithm for combined angiographic/perfusion imaging. This algorithm will be developed (Aim 1) and validated (Aim 2) in a porcine model. The resulting algorithm will then be compared with radionuclide perfusion imaging and cardiac catheterization imaging in cardiac patients (Aim 3). Determination of the physiological significance of coronary artery stenoses is critical for optimizing revascularization decisions in CAD patients. The successful conclusion of this research will be a noninvasive diagnostic imaging exam for the detection and assessment of coronary artery disease.